After todays unmasking of the ‘real’ BIA 10-2474 I ran it through some of the online tools used earlier and now I have found software issues – that darn pyridine 1 -oxide is not liked by some of the websites probably because they use the same SMILES to structure software plugin?

SwissTarget Prediction identifies FAAH1 top followed by histone deacetylases. SEA and Molinspiration have issues with the N-O and produces a N=O so that predictions are spurious. MetaPrint2D-React proposes hydroxylation on the cyclohexyl, HitPick suggests a lipase is the target(?), and similarity against a library of synthetic cannabinoids suggests that this molecule is not very similar with a maximal Tanimoto similarity of 0.6.

So no real clues – frustrating that SEA is not able to convert to the right structure and generate a prediction. SwissTargetPrediction still suggests the compound may hit other targets besides FAAH1. Which makes one ask is the N-oxide forming a protein adduct also? Or is something else responsible for the toxicity? Why did they use an pyridine 1 -oxide as a potential drug?

++Thanks to Alex Clark I can now add the predictions with the Open Bayesian Models. Here is a screen shot along with an image of the clustering for the highest predicted human target macrophage-stimulating protein receptor.

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SEA (2007 version) uses the molinspiration convention. There are two conventions in widespread use. Same for -N(=O)(=O). It is a convention. A very old one. I think it is a misunderstanding to say that it has “issues”. N-oxides are not well interpreted (do not act like) zwitterions, either, for instance, so that representation has “issues” too.

I have no real dog in this fight. We use rdkit these days, which uses the convention you prefer. I just think throwing around “issues” is unhelpful.

Quoting:
“A short note is in order about aromatic nitrogens, a common source of confusion in chemical information systems. All three common types of aromatic nitrogen may be specified with the aromatic nitrogen symbol n. Archetypical examples are pyridine, pyridine-N-oxide, and pyrrole.”

So just to say, this is an old topic.

sean says:

But can it be fixed? I dont think I am throwing around issues but clearly it limited utility here – I was actually trying to highlight tools that could be useful in cases like this. All was fine until the structure changed. No specific fight to pick with SEA as it seems useful.. Note not all tools hit this wall. If there is a better version I need to use please link me and will gladly try and blog about it.

cdsouthan says:

I agree that “issue” has become sematically overloaded. I merely meant “unexpected behaviour” (or quirk even). I have to declare I have no experience with SEA or RDkit (but would like to have) and tend to work across the PubChem, Chemicalize, ChEMBL/SureChEMBL, OpenBabel axis. For these the BIA 10-2474 IUPAC string was not only conistant in search result connectivity, they even matched the same N-oxide +/- rendering that Bial used in their patent image (and SureChEMBL had extracted). So I dont have an “issue” with SciFinder but simply was not expecting it to refuse the SMILES copy-over from a CID, consequently force a valency correction and render a double bond. The seach result seem consistant so I suppose shouldn’t grumble just because its not so PubChem like.

Lauren says:

I think the real question is-let’s assume the current structure is correct. How did such a major toxicity like vascular stroke arise? Let’s also assume for now that there is not a contaminant. Usually the brain is a somewhat protected compartment even with CNS drugs. Ordinarily you expect higher concentrations to occur and liver heart lung and kidney and spleen, highly perfused organs and secondary compartment “sharing” with the brain and CSF. Somehow unless something major was missed or unreported earlier in the trial, the brain seems to be providing both an index toxicity and also a catastrophic event with very little time between any premonitory signs and brain damage. I don’t think we have ever seen such a catastrophe occur to the brain without systemic toxicity. FIAU hit the liver as the example.
My earlier suggestion was not that this drug had cannabinoid agonist activity rather it may be acting as an accumulating irreversible inactivator of FAAH , resulting in extreme levels of natural CB1 ligand agonist, Anandamide. This would lead to exaggerated action at CB1 receptor, thus simulating some extreme examples of synthetic cannabinoids which have been associated with stroke in a possibly under reported fashion see Rose et al.

The drug company now mentions that this compound is irreversible. The pyridine N-oxide is flagged by the Lilly MedChem Rules and is border line with regard to the Pfizer 3/75 rule as seen after computations with FAF-drugs. This alert, plus some unclear metabolism, plus the very high daily dose (for a compound that contains such an alert) could explain this drama